Cisatracurium besylate has the chemical name (1R,1′R,2R,2′R)-2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)]methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium dibenzenesulfonate and is represented by the structural formula (I) below:

Cisatracurium besylate is the dibenzenesulfonate salt of 1R-cis,1′R-cis isomer of atracurium (i.e., two molecules of benzenesulfonate per one diammonium molecule of cisatracurium). The atracurium molecule has four chiral centers, which should theoretically allow for 16 possible isomers. Due to the symmetry of the molecule, however, the number of possible isomers is reduced to 10. Cisatracurium besylate is one of the 10 possible isomers of atracurium besylate and may constitute approximately 15% of that mixture when produced by a conventional synthesis process.
Cisatracurium besylate is a nondepolarizing neuromuscular blocking agent indicated for inpatients and outpatients as an adjunct to general anesthesia, to facilitate tracheal intubation, and to provide skeletal muscle relaxation during surgery or mechanical ventilation in the Intensive Care Unit (ICU). Cisatracurium besylate possesses an activity that is superior to atracurium besylate, with significantly reduced side effects. Cisatracurium besylate is marketed in the United States and Europe by Glaxo Wellcome and Abbott Laboratories under the trade name NIMBEX®, which is a sterile, non-pyrogenic aqueous solution that is adjusted to pH 3.25 to 3.65 with benzenesulfonic acid. The drug is provided in 2.5 ml, 5 ml and 10 ml ampoules having a strength of 2 mg/ml cisatracurium besylate. A 30 ml vial containing 5 mg/ml cisatracurium besylate is also available.
Cisatracurium besylate slowly loses potency with time at a rate of approximately. 5% per year under refrigeration (5° C.). NIMBEX® should be refrigerated at 2° to 8° C. (36° to 46° F.) to preserve potency. The rate of loss in potency increases to approximately 5% per month at 25° C. (77° F.).
Atracurium besylate, otherwise known as 2,2′-[1,5-pentanediylbis[oxy(3-oxo-3,1-propanediyl)]]bis[1-[(3,4-dimethoxyphenyl)methyl]-1,2,3,4-tetrahydro-6,7-dimethoxy-2-methyl-isoquinolinium dibenzenesulfonate, is disclosed in U.S. Pat. No. 4,179,507 (hereinafter U.S. '507). U.S. '507 describes a series of bis veratryl isoquinolinium quaternary ammonium salts, preferably among them is atracurium besylate.
The synthesis of atracurium besylate, as taught in U.S. '507, involves the coupling of (±)-tetrahydropapaverine base, compound (II), with 1,5-pentamethylene diacrylate, compound (III). Treatment of the resulting tertiary amine base with oxalic acid results in the isolation of N,N′-4,10-dioxa-3,11-dioxotridecylene-1,13-bis-tetrahydro-papaverine dioxalate, compound (IV). The dioxalate salt (compound (IV) is converted to the free base, compound (V), with sodium bicarbonate solution and extracted into toluene. After evaporation of the toluene, the residue is dissolved in acetonitrile and treated with methyl benzenesulfonate. The addition of diethyl ether results in the precipitation of atracurium besylate, compound (VI), which is subsequently filtered and dried. Scheme 1 below illustrates the chemical pathway described above.

U.S. '507 teaches that the stereoisomerism of atracurium besylate (VI) may be partly controlled by controlling stereochemical configuration of compound (II) to provide the tertiary amine base (V) of a RR-, SS-, or RS-(meso) configuration. The quaternization process introduces 2 additional asymmetric centers and produces a mixture of stereoisomers. U.S. '507 does not describe separating stereoisomers from the mixture.
The preparation of cisatracurium besylate is disclosed in U.S. Pat. Nos. 5,453,510 and 5,556,978, wherein the (1R,1′R)-atracurium besylate mixture is subjected to preparative HPLC column chromatography on silica using a mixture of dichloromethane, methanol and benzenesulfonic acid in the ratio of 4000:500:0.25 as the eluant. The fractions containing the required isomer are collected and further processed to afford cisatracurium besylate possessing an isomeric purity of about 99%.
Conventional HPLC separation procedures suffer from the disadvantage that they require specialized equipment, which is relatively expensive and time-consuming to operate, and may not be suitable for large scale operations. There is, therefore, a need for an improved method for chromatographically purifying cisatracurium besylate, which is more suitable for large scale operations. The present invention provides such a method.